Alternative splicing (AS) is regulated by a myriad of RNA-binding proteins (RBPs) in a coordinated manner. However, most studies characterize RBPs individually. In this issue of Genes & Development, Peyda and colleagues (doi:10.1101/gad.352105.124) revealed how the LASR complex, consisting of multiple RBPs, regulates AS by recognizing multipart sequences. Their approach may be applicable to studying the combinatorial effects of other RBPs, which is critical for cracking the splicing code.
{"title":"RNA-binding proteins: it's better to play in a band","authors":"Joshua Jeong, Klemens J. Hertel, Yongsheng Shi","doi":"10.1101/gad.352667.125","DOIUrl":"https://doi.org/10.1101/gad.352667.125","url":null,"abstract":"Alternative splicing (AS) is regulated by a myriad of RNA-binding proteins (RBPs) in a coordinated manner. However, most studies characterize RBPs individually. In this issue of <em>Genes & Development</em>, Peyda and colleagues (doi:10.1101/gad.352105.124) revealed how the LASR complex, consisting of multiple RBPs, regulates AS by recognizing multipart sequences. Their approach may be applicable to studying the combinatorial effects of other RBPs, which is critical for cracking the splicing code.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"10 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joyce Wolf van der Meer, Axelle Larue, Jan A. van der Knaap, Gillian E. Chalkley, Ayestha Sijm, Leila Beikmohammadi, Elena N. Kozhevnikova, Aniek van der Vaart, Ben C. Tilly, Karel Bezstarosti, Dick H.W. Dekkers, Wouter A.S. Doff, P. Jantine van de Wetering-Tieleman, Kristina Lanko, Tahsin Stefan Barakat, Tim Allertz, Jeffrey van Haren, Jeroen A.A. Demmers, Yaser Atlasi, C. Peter Verrijzer
Pathogenic variants in the ubiquitin-specific protease 7 (USP7) gene cause a neurodevelopmental disorder called Hao-Fountain syndrome. However, it remains unclear which of USP7's pleiotropic functions are relevant for neurodevelopment. Here, we present a combination of quantitative proteomics, transcriptomics, and epigenomics to define the USP7 regulatory circuitry during neuronal differentiation. USP7 activity is required for the transcriptional programs that direct both the differentiation of embryonic stem cells into neural stem cells and the neuronal differentiation of SH-SY5Y neuroblastoma cells. USP7 controls the dosage of the Polycomb monubiquitylated histone H2A lysine 119 (H2AK119ub1) ubiquitin ligase complexes ncPRC1.1 and ncPRC1.6. Loss-of-function experiments revealed that BCOR–ncPRC1.1, but not ncPRC1.6, is a key effector of USP7 during neuronal differentiation. Indeed, BCOR–ncPRC1.1 mediates a major portion of USP7-dependent gene regulation during this process. Besides providing a detailed map of the USP7 regulome during neurodifferentiation, our results suggest that USP7- and ncPRC1.1-associated neurodevelopmental disorders involve dysregulation of a shared epigenetic network.
{"title":"Hao-Fountain syndrome protein USP7 controls neuronal differentiation via BCOR–ncPRC1.1","authors":"Joyce Wolf van der Meer, Axelle Larue, Jan A. van der Knaap, Gillian E. Chalkley, Ayestha Sijm, Leila Beikmohammadi, Elena N. Kozhevnikova, Aniek van der Vaart, Ben C. Tilly, Karel Bezstarosti, Dick H.W. Dekkers, Wouter A.S. Doff, P. Jantine van de Wetering-Tieleman, Kristina Lanko, Tahsin Stefan Barakat, Tim Allertz, Jeffrey van Haren, Jeroen A.A. Demmers, Yaser Atlasi, C. Peter Verrijzer","doi":"10.1101/gad.352272.124","DOIUrl":"https://doi.org/10.1101/gad.352272.124","url":null,"abstract":"Pathogenic variants in the ubiquitin-specific protease 7 (<em>USP7</em>) gene cause a neurodevelopmental disorder called Hao-Fountain syndrome. However, it remains unclear which of USP7's pleiotropic functions are relevant for neurodevelopment. Here, we present a combination of quantitative proteomics, transcriptomics, and epigenomics to define the USP7 regulatory circuitry during neuronal differentiation. USP7 activity is required for the transcriptional programs that direct both the differentiation of embryonic stem cells into neural stem cells and the neuronal differentiation of SH-SY5Y neuroblastoma cells. USP7 controls the dosage of the Polycomb monubiquitylated histone H2A lysine 119 (H2AK119ub1) ubiquitin ligase complexes ncPRC1.1 and ncPRC1.6. Loss-of-function experiments revealed that BCOR–ncPRC1.1, but not ncPRC1.6, is a key effector of USP7 during neuronal differentiation. Indeed, BCOR–ncPRC1.1 mediates a major portion of USP7-dependent gene regulation during this process. Besides providing a detailed map of the USP7 regulome during neurodifferentiation, our results suggest that USP7- and ncPRC1.1-associated neurodevelopmental disorders involve dysregulation of a shared epigenetic network.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"15 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mammalian DNA replication origins have been historically difficult to identify and their determinants are still unresolved. Here, we first review methods developed over the last decades to map replication initiation sites either directly via initiation intermediates or indirectly via determining replication fork directionality profiles. We also discuss the factors that may specify these sites as replication initiation sites. Second, we address the controversy that has emerged from these results over whether origins are narrowly defined and localized to specific sites or are more dispersed and organized into broad zones. Ample evidence in favor of both scenarios currently creates an impression of unresolved confusion in the field. We attempt to formulate a synthesis of both models and to reconcile discrepant findings. It is evident that not only one approach is sufficient in isolation but that the combination of several is instrumental toward understanding initiation sites in mammalian genomes. We argue that an aggregation of several individual and often inefficient initiation sites into larger initiation zones and the existence of efficient unidirectional initiation sites and fork stalling at the borders of initiation zones can reconcile the different observations.
{"title":"The double life of mammalian DNA replication origins","authors":"Olivier Hyrien, Guillaume Guilbaud, Torsten Krude","doi":"10.1101/gad.352227.124","DOIUrl":"https://doi.org/10.1101/gad.352227.124","url":null,"abstract":"Mammalian DNA replication origins have been historically difficult to identify and their determinants are still unresolved. Here, we first review methods developed over the last decades to map replication initiation sites either directly via initiation intermediates or indirectly via determining replication fork directionality profiles. We also discuss the factors that may specify these sites as replication initiation sites. Second, we address the controversy that has emerged from these results over whether origins are narrowly defined and localized to specific sites or are more dispersed and organized into broad zones. Ample evidence in favor of both scenarios currently creates an impression of unresolved confusion in the field. We attempt to formulate a synthesis of both models and to reconcile discrepant findings. It is evident that not only one approach is sufficient in isolation but that the combination of several is instrumental toward understanding initiation sites in mammalian genomes. We argue that an aggregation of several individual and often inefficient initiation sites into larger initiation zones and the existence of efficient unidirectional initiation sites and fork stalling at the borders of initiation zones can reconcile the different observations.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"40 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
External signals from the thymic microenvironment and the activities of lineage-specific transcription factors (TFs) instruct T-cell versus innate lymphoid cell (ILC) fates. However, mechanistic insights into how factors such as Notch1–Delta-like-4 (Dll4) signaling and E-protein TFs collaborate to establish T-cell identity remain rudimentary. Using multiple in vivo approaches and single-cell multiome analysis, we identified a feedback amplifier circuit that specifies fetal and adult T-cell fates. In early T progenitors (ETPs) in the fetal thymus, Notch signaling minimally lowered E-protein antagonist Id2 levels, and high Id2 abundance favored the differentiation of ETPs into ILCs. Conversely, in the adult thymus, Notch signaling markedly decreased Id2 abundance in ETPs, substantially elevating E-protein DNA binding and in turn promoting the activation of a T-cell lineage-specific gene expression program linked with V(D)J gene recombination and T-cell receptor signaling. Our findings indicate that, in the fetal versus the adult thymus, a simple feedback amplifier circuit dictated by Notch-mediated signals and Id2 abundance enforces T-cell identity and suppresses ILC development.
{"title":"A feedback amplifier circuit with Notch and E2A orchestrates T-cell fate and suppresses the innate lymphoid cell lineages during thymic ontogeny","authors":"Kazuko Miyazaki, Kenta Horie, Hitomi Watanabe, Reiko Hidaka, Rinako Hayashi, Norihito Hayatsu, Kentaro Fujiwara, Rei Kuwata, Takuya Uehata, Yotaro Ochi, Makoto Takenaka, Risa Karakida Kawaguchi, Koichi Ikuta, Osamu Takeuchi, Seishi Ogawa, Katsuto Hozumi, Georg A. Holländer, Gen Kondoh, Taishin Akiyama, Masaki Miyazaki","doi":"10.1101/gad.352111.124","DOIUrl":"https://doi.org/10.1101/gad.352111.124","url":null,"abstract":"External signals from the thymic microenvironment and the activities of lineage-specific transcription factors (TFs) instruct T-cell versus innate lymphoid cell (ILC) fates. However, mechanistic insights into how factors such as Notch1–Delta-like-4 (Dll4) signaling and E-protein TFs collaborate to establish T-cell identity remain rudimentary. Using multiple in vivo approaches and single-cell multiome analysis, we identified a feedback amplifier circuit that specifies fetal and adult T-cell fates. In early T progenitors (ETPs) in the fetal thymus, Notch signaling minimally lowered E-protein antagonist <em>Id2</em> levels, and high <em>Id2</em> abundance favored the differentiation of ETPs into ILCs. Conversely, in the adult thymus, Notch signaling markedly decreased <em>Id2</em> abundance in ETPs, substantially elevating E-protein DNA binding and in turn promoting the activation of a T-cell lineage-specific gene expression program linked with V(D)J gene recombination and T-cell receptor signaling. Our findings indicate that, in the fetal versus the adult thymus, a simple feedback amplifier circuit dictated by Notch-mediated signals and <em>Id2</em> abundance enforces T-cell identity and suppresses ILC development.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"41 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Núria de la Iglesia, Genevieve Konopka, Sidharth V. Puram, Jennifer A. Chan, Robert M. Bachoo, Mingjian J. You, David E. Levy, Ronald A. DePinho, Azad Bonni
Genes & Development 22: 449–462 (2008)
{"title":"Corrigendum: Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway","authors":"Núria de la Iglesia, Genevieve Konopka, Sidharth V. Puram, Jennifer A. Chan, Robert M. Bachoo, Mingjian J. You, David E. Levy, Ronald A. DePinho, Azad Bonni","doi":"10.1101/gad.352503.124","DOIUrl":"https://doi.org/10.1101/gad.352503.124","url":null,"abstract":"<strong>Genes & Development 22:</strong> 449–462 (2008)","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"39 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parham Peyda, Chia-Ho Lin, Kelechi Onwuzurike, Douglas L. Black
The Rbfox proteins regulate alternative pre-mRNA splicing by binding to the RNA element GCAUG. In the nucleus, most of Rbfox is bound to the large assembly of splicing regulators (LASR), a complex of RNA-binding proteins that recognize additional RNA motifs. However, it remains unclear how the different subunits of the Rbfox/LASR complex act together to bind RNA and regulate splicing. We used a nuclease protection assay to map the transcriptome-wide footprints of Rbfox1/LASR on nascent cellular RNA. In addition to GCAUG, Rbfox1/LASR binds RNA motifs for LASR subunits hnRNPs M, H/F, and C and Matrin3. These elements are often arranged in tandem, forming multipart modules of RNA motifs. To distinguish contact sites of Rbfox1 from the LASR subunits, we analyzed a mutant Rbfox1(F125A) that has lost RNA binding but remains associated with LASR. Rbfox1(F125A)/LASR complexes no longer interact with GCAUG but retain binding to RNA elements for LASR. Splicing analyses reveal that in addition to activating exons through adjacent GCAUG elements, Rbfox can also stimulate exons near binding sites for LASR subunits. Minigene experiments demonstrate that these diverse elements produce a combined regulatory effect on a target exon. These findings illuminate how a complex of RNA-binding proteins can decode combinatorial splicing regulatory signals by recognizing groups of tandem RNA elements.
{"title":"The Rbfox1/LASR complex controls alternative pre-mRNA splicing by recognition of multipart RNA regulatory modules","authors":"Parham Peyda, Chia-Ho Lin, Kelechi Onwuzurike, Douglas L. Black","doi":"10.1101/gad.352105.124","DOIUrl":"https://doi.org/10.1101/gad.352105.124","url":null,"abstract":"The Rbfox proteins regulate alternative pre-mRNA splicing by binding to the RNA element GCAUG. In the nucleus, most of Rbfox is bound to the large assembly of splicing regulators (LASR), a complex of RNA-binding proteins that recognize additional RNA motifs. However, it remains unclear how the different subunits of the Rbfox/LASR complex act together to bind RNA and regulate splicing. We used a nuclease protection assay to map the transcriptome-wide footprints of Rbfox1/LASR on nascent cellular RNA. In addition to GCAUG, Rbfox1/LASR binds RNA motifs for LASR subunits hnRNPs M, H/F, and C and Matrin3. These elements are often arranged in tandem, forming multipart modules of RNA motifs. To distinguish contact sites of Rbfox1 from the LASR subunits, we analyzed a mutant Rbfox1(F125A) that has lost RNA binding but remains associated with LASR. Rbfox1(F125A)/LASR complexes no longer interact with GCAUG but retain binding to RNA elements for LASR. Splicing analyses reveal that in addition to activating exons through adjacent GCAUG elements, Rbfox can also stimulate exons near binding sites for LASR subunits. Minigene experiments demonstrate that these diverse elements produce a combined regulatory effect on a target exon. These findings illuminate how a complex of RNA-binding proteins can decode combinatorial splicing regulatory signals by recognizing groups of tandem RNA elements.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"207 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neuronal maturation is guided by changes in the chromatin landscape that control developmental gene expression programs. Histone bivalency, the co-occurrence of activating and repressive histone modifications, has emerged as an epigenetic feature of developmentally regulated genes during neuronal maturation. Although initially associated with early embryonic development, recent studies have shown that histone bivalency also exists in differentiated and mature neurons. In this review, we discuss methods to study bivalency in specific populations of neurons and summarize emerging studies on the function of bivalency in central nervous system neuronal maturation and in adult neurons.
{"title":"Histone bivalency in CNS development","authors":"Kärt Mätlik, Eve-Ellen Govek, Mary E. Hatten","doi":"10.1101/gad.352306.124","DOIUrl":"https://doi.org/10.1101/gad.352306.124","url":null,"abstract":"Neuronal maturation is guided by changes in the chromatin landscape that control developmental gene expression programs. Histone bivalency, the co-occurrence of activating and repressive histone modifications, has emerged as an epigenetic feature of developmentally regulated genes during neuronal maturation. Although initially associated with early embryonic development, recent studies have shown that histone bivalency also exists in differentiated and mature neurons. In this review, we discuss methods to study bivalency in specific populations of neurons and summarize emerging studies on the function of bivalency in central nervous system neuronal maturation and in adult neurons.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"26 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yike Huang, Marjon J.A.M. Verstegen, Sjoerd J.D. Tjalsma, Peter H.L. Krijger, Kavvya Gupta, Minhee Park, Alistair Boettiger, Wouter de Laat
Enhancers are tissue-specific regulatory DNA elements that can activate transcription of genes over distance. Their target genes most often are located in the same contact domain—chromosomal entities formed by cohesin DNA loop extrusion and typically flanked by CTCF-bound boundaries. Enhancers shared by multiple unrelated genes are underexplored but may be more common than anticipated. Here, we analyzed the interplay between an enhancer and two distal functionally unrelated genes residing at opposite domain boundaries. The enhancer strongly activated their expression and supported their frequent interactions. Cohesin structured the domain and supported their transcription, but the genes did not rely on each other's transcription or show gene competition. Deleting either domain boundary not only extended the contact domain but led to reduced contacts within the original domain and reduction in the expression of both genes. Conversely, by isolating either gene with the enhancer in shorter domains, through insertion of new CTCF boundaries, intradomain contact frequencies increased, and the gene isolated with the enhancer was upregulated. Collectively, this shows that an enhancer can independently activate unrelated distal genes and that long-range gene regulation benefits from operating in small contact domains.
{"title":"Two unrelated distal genes activated by a shared enhancer benefit from localizing inside the same small topological domain","authors":"Yike Huang, Marjon J.A.M. Verstegen, Sjoerd J.D. Tjalsma, Peter H.L. Krijger, Kavvya Gupta, Minhee Park, Alistair Boettiger, Wouter de Laat","doi":"10.1101/gad.352235.124","DOIUrl":"https://doi.org/10.1101/gad.352235.124","url":null,"abstract":"Enhancers are tissue-specific regulatory DNA elements that can activate transcription of genes over distance. Their target genes most often are located in the same contact domain—chromosomal entities formed by cohesin DNA loop extrusion and typically flanked by CTCF-bound boundaries. Enhancers shared by multiple unrelated genes are underexplored but may be more common than anticipated. Here, we analyzed the interplay between an enhancer and two distal functionally unrelated genes residing at opposite domain boundaries. The enhancer strongly activated their expression and supported their frequent interactions. Cohesin structured the domain and supported their transcription, but the genes did not rely on each other's transcription or show gene competition. Deleting either domain boundary not only extended the contact domain but led to reduced contacts within the original domain and reduction in the expression of both genes. Conversely, by isolating either gene with the enhancer in shorter domains, through insertion of new CTCF boundaries, intradomain contact frequencies increased, and the gene isolated with the enhancer was upregulated. Collectively, this shows that an enhancer can independently activate unrelated distal genes and that long-range gene regulation benefits from operating in small contact domains.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"20 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Long interspersed element-1 (LINE-1) retrotransposons are abundant transposable elements in mammals and significantly influence chromosome structure, chromatin organization, and 3D genome architecture. In this issue of Genes & Development, Ataei et al. (doi:10.1101/gad.351979.124) identify a homininae-specific LINE-1 element within nucleolar ogranizer regions (NORs) that is specifically transcribed in naïve human embryonic stem cells. Deletion or silencing of this element disrupts nucleolar organization and function and alters cellular identity. These findings provide novel insights into the role of retrotransposons in genome organization and suggest that individual LINE-1 elements may have evolved specialized roles.
Long interspersed element-1 （LINE-1）逆转录转座子是哺乳动物中丰富的转座子，对染色体结构、染色质组织和三维基因组结构有重要影响。在本期的《基因》杂志上；Development， Ataei等人（doi:10.1101/gad.351979.124）鉴定了在naïve人类胚胎干细胞中特异性转录的核仁增粒区（NORs）中具有人科特异性的LINE-1元件。该元件的缺失或沉默会破坏核仁的组织和功能，并改变细胞的身份。这些发现为逆转录转座子在基因组组织中的作用提供了新的见解，并表明单个LINE-1元件可能进化出专门的作用。
{"title":"LINE-1, the NORth star of nucleolar organization","authors":"Misaki Matsuo, Gael Cristofari","doi":"10.1101/gad.352583.124","DOIUrl":"https://doi.org/10.1101/gad.352583.124","url":null,"abstract":"Long interspersed element-1 (LINE-1) retrotransposons are abundant transposable elements in mammals and significantly influence chromosome structure, chromatin organization, and 3D genome architecture. In this issue of <em>Genes & Development</em>, Ataei et al. (doi:10.1101/gad.351979.124) identify a homininae-specific LINE-1 element within nucleolar ogranizer regions (NORs) that is specifically transcribed in naïve human embryonic stem cells. Deletion or silencing of this element disrupts nucleolar organization and function and alters cellular identity. These findings provide novel insights into the role of retrotransposons in genome organization and suggest that individual LINE-1 elements may have evolved specialized roles.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"64 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sushant Bangru, Jackie Chen, Nicholas Baker, Diptatanu Das, Ullas V. Chembazhi, Jessica M. Derham, Sandip Chorghade, Waqar Arif, Frances Alencastro, Andrew W. Duncan, Russ P. Carstens, Auinash Kalsotra
Hepatocyte polyploidy and maturity are critical to acquiring specialized liver functions. Multiple intracellular and extracellular factors influence ploidy, but how they cooperate temporally to steer liver polyploidization and maturation or how post-transcriptional mechanisms integrate into these paradigms is unknown. Here, we identified an important regulatory hierarchy in which postnatal activation of epithelial splicing regulatory protein 2 (ESRP2) stimulates processing of liver-specific microRNA (miR-122) to facilitate polyploidization, maturation, and functional competence of hepatocytes. By determining transcriptome-wide protein–RNA interactions in vivo and integrating them with single-cell and bulk hepatocyte RNA-seq data sets, we delineated an ESRP2-driven RNA processing program that drives sequential replacement of fetal-to-adult transcript isoforms. Specifically, ESRP2 binds the primary miR-122 host gene transcript to promote its processing/biogenesis. Combining constitutive and inducible ESRP2 gain- and loss-of-function mouse models with miR-122 rescue experiments, we demonstrated that timed activation of ESRP2 augments the miR-122-driven program of cytokinesis failure, ensuring the proper onset and extent of hepatocyte polyploidization.
{"title":"ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation","authors":"Sushant Bangru, Jackie Chen, Nicholas Baker, Diptatanu Das, Ullas V. Chembazhi, Jessica M. Derham, Sandip Chorghade, Waqar Arif, Frances Alencastro, Andrew W. Duncan, Russ P. Carstens, Auinash Kalsotra","doi":"10.1101/gad.352129.124","DOIUrl":"https://doi.org/10.1101/gad.352129.124","url":null,"abstract":"Hepatocyte polyploidy and maturity are critical to acquiring specialized liver functions. Multiple intracellular and extracellular factors influence ploidy, but how they cooperate temporally to steer liver polyploidization and maturation or how post-transcriptional mechanisms integrate into these paradigms is unknown. Here, we identified an important regulatory hierarchy in which postnatal activation of epithelial splicing regulatory protein 2 (ESRP2) stimulates processing of liver-specific microRNA (<em>miR-122</em>) to facilitate polyploidization, maturation, and functional competence of hepatocytes. By determining transcriptome-wide protein–RNA interactions in vivo and integrating them with single-cell and bulk hepatocyte RNA-seq data sets, we delineated an ESRP2-driven RNA processing program that drives sequential replacement of fetal-to-adult transcript isoforms. Specifically, ESRP2 binds the primary <em>miR-122</em> host gene transcript to promote its processing/biogenesis. Combining constitutive and inducible ESRP2 gain- and loss-of-function mouse models with <em>miR-122</em> rescue experiments, we demonstrated that timed activation of ESRP2 augments the <em>miR-122</em>-driven program of cytokinesis failure, ensuring the proper onset and extent of hepatocyte polyploidization.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"319 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：